m6A Modification-Mediated Regulation of DCAF13 Promotes Glycolytic Metabolism and Drives Hepatocellular Carcinoma Progression via Interaction With G6PD.

[BACKGROUND] Hepatocellular carcinoma (HCC) is a highly aggressive malignancy with poor prognosis due to enhanced glycolytic metabolism and tumor heterogeneity. Identifying key regulators of glycolysis may provide novel therapeutic targets.

[METHODS] We investigated the role of DCAF13 in HCC using bioinformatics analysis, CRISPR/Cas9-mediated knockout, overexpression assays, in vitro and in vivo functional studies, and molecular dynamics simulations. m6A modification of DCAF13 was analyzed through MeRIP-qPCR and RIP assays.

[RESULTS] DCAF13 was significantly upregulated in HCC tissues and associated with poor prognosis. Functional assays revealed that DCAF13 promotes HCC cell proliferation, migration, invasion, and tumor growth. Mechanistically, DCAF13 directly interacts with glucose-6-phosphate dehydrogenase (G6PD), enhancing glycolytic flux. Molecular dynamics simulations confirmed the stability of the DCAF13-G6PD complex. Furthermore, METTL3-mediated m6A modification and YTHDF1 binding stabilized DCAF13 mRNA, maintaining its high expression. Silencing METTL3 or YTHDF1 reduced DCAF13 levels and impaired its oncogenic function.

[CONCLUSIONS] We identified a METTL3-DCAF13-YTHDF1-G6PD axis that promotes glycolytic reprogramming and HCC progression. DCAF13 may serve as a promising biomarker and therapeutic target for metabolic intervention in HCC.